A1005
Title: The causality and dynamics of gene regulation during macrophage-neutrophil differentiation
Authors: Manu Manu - University of North Dakota (United States) [presenting]
Yen Lee Loh - University of North Dakota (United States)
Trevor Long - University of North Dakota (United States)
Nimasha Samarawickrama - University of North Dakota (United States)
Abstract: During gene regulation, DNA accessibility is thought to limit the availability of transcription factor (TF) binding sites, while TFs can increase DNA accessibility to recruit additional factors that upregulate gene expression. Given this interplay, the causative regulatory events in the modulation of gene expression remain unknown for the vast majority of genes. The causality of gene regulation is investigated during macrophage-neutrophil differentiation using joint RNA-Seq and ATAC-Seq time series datasets. It is shown using an unsupervised learning technique that only 10 distinct temporal expression patterns are sufficient to recapitulate the expression of ~36,000 transcripts with high fidelity. Furthermore, information transfer during differentiation was found to occur in cascading waves of gene expression culminating in the permanent turning on of certain genes after ~80h. The genes enriched in each wave suggest a characteristic order of physiological remodeling-signal transduction, translation and mRNA processing, metabolism, and, ultimately, myeloid phenotypic processes. It is also found that gene expression dynamics do not observe any strict relationship with the dynamics of the accessibility of enhancers or promoters, varying from highly positively correlated to uncorrelated, to highly negatively correlated. In a detailed analysis of a key neutrophil gene, Cebpa, it is shown that TF occupancy rather than DNA accessibility is the causal driver of gene expression.
